Preventative and therapeutic potential of animal milk components against COVID-19: A comprehensive review

The paper addresses whether animal milk and its bioactive constituents can provide preventative and therapeutic benefits against COVID-19. It frames COVID-19’s global burden and the need for safe, economical, orally available immunomodulators and antivirals that can be used in outpatient settings to reduce hospitalizations. The review aims to summarize evidence on immunomodulatory, antiviral, anti-inflammatory, antithrombotic, and supportive roles of animal milk components—proteins, fats, carbohydrates (oligosaccharides and glycosaminoglycans), vitamins, and minerals—in the context of viral infections with a special emphasis on SARS-CoV-2.

The review synthesizes a wide body of literature on milk-derived bioactives: caseins and whey proteins (including lactoferrin, lactoperoxidase, mucins), peptides generated by enzymatic hydrolysis or fermentation, milk fats such as glycerol monolaurate and omega-3 long-chain PUFAs (EPA, DHA), milk oligosaccharides and glycosaminoglycans, and micronutrients (fat- and water-soluble vitamins and macro/microminerals). It compiles in vitro, in silico, animal, and limited human evidence demonstrating immunomodulation, antiviral activity against diverse DNA/RNA viruses (HSV, RSV, influenza, rotavirus, HCV, HIV, coronaviruses), anti-inflammatory actions relevant to cytokine storm, and effects on coagulation. Specific mechanisms include interference with viral entry receptors (ACE2, DPP-4, HSPG), inhibition of viral proteases (3CLpro/Mpro), reduction of furin activity and spike-ACE2 binding, direct virucidal effects on enveloped viruses, modulation of cytokine profiles, support of antioxidant defenses, and antiplatelet/antithrombotic activities. The review also discusses variability of bioactive composition across species (cow, buffalo, goat, sheep, camel, donkey, equine) and lactation stages, and notes parallels between human and animal milk glycans.

Narrative comprehensive review of published studies across mechanistic (in silico docking), cellular (in vitro), animal (in vivo), and clinical/observational reports. No new experiments or data analyses were performed. Ethical approval and data sharing were not applicable. The article collates findings from diverse sources to propose potential prophylactic and adjunctive therapeutic roles of animal milk components in COVID-19.

- Milk proteins (caseins) generate bioactive peptides (e.g., isracidin, β-casomorphins, κ-casein-derived glycomacropeptide) with immunomodulatory, anti-inflammatory, and antithrombotic properties; several casein peptides show antiviral effects against enteric and respiratory viruses and may inhibit SARS-CoV-2 entry in silico. - Whey proteins and fractions (lactoferrin, α-lactalbumin, β-lactoglobulin, mucins) exhibit broad antiviral activity. Human and bovine lactoferrin (LF) can block viral attachment by binding heparan sulfate proteoglycans (HSPG) and may interfere with ACE2–spike interactions; bovine LF inhibited SARS pseudovirus entry (IC50 ~0.7 mM) and showed in vitro activity against SARS-CoV-2 and common human coronaviruses. BLF may synergize with remdesivir (reported ~8-fold enhancement in cell culture). - Whey peptides derived from BLG/ALA and other milk proteins demonstrate in silico inhibition of ACE2, DPP-4, and SARS-CoV-2 main protease (3CLpro/Mpro); buffalo milk-derived peptides may block spike–ACE2 and affect replication/assembly steps. - WPC supplementation reduced lung oxidative injury, furin activity, and spike–ACE2 binding in a rodent model; microfiltered WPI/WPC stimulate lymphocyte proliferation and enhance humoral responses in animals. - Lactoperoxidase (LPO) system generates hypothiocyanite with virucidal activity against enveloped viruses; time- and dose-dependent in vitro killing against SARS-CoV-2 has been reported, with modest enhancement by LF. - Lysozyme exhibits anti-inflammatory and potential antiviral entry-blocking effects in ocular and corneal epithelial models exposed to SARS-CoV-2 spike. - Milk oligosaccharides (MOs), particularly sialylated glycans, can act as decoy receptors and prebiotics; human and animal MOs target sialic-acid dependent pathogens and may interfere with SARS-CoV-2 co-receptor interactions (e.g., HS, sialic acids). GAGs (heparin/HS, CS, DS) display antiviral effects; exogenous HS/heparin can inhibit SARS-related coronavirus infection in vitro. - Milk fats: Glycerol monolaurate (GML) is virucidal against enveloped viruses and modulates T-cell cytokine output; omega-3 LC-PUFAs (EPA/DHA) resolve inflammation via SPMs (resolvins, protectins, maresins), with evidence for benefit in ARDS, potentially relevant to COVID-19. - Vitamins: A (retinoic acid) supports mucosal immunity and lung repair; D modulates ACE2 and immune responses and is linked to respiratory infection outcomes; E provides antioxidant/anti-ferroptotic effects; K influences coagulation and inflammation and deficiency correlates with worse COVID-19 outcomes; B-complex (notably B1, B6, B9, B12) may mitigate thrombosis/inflammation and show in silico binding to viral protease; C supports antiviral immunity and may reduce ICU stay duration. - Minerals: Calcium and phosphorus status relate to disease severity; magnesium supports anti-inflammatory and vitamin D activation; sodium/potassium disturbances (hyponatremia/hypokalemia) relate to worse outcomes; zinc inhibits coronavirus RdRp and modulates inflammation; selenium status correlates with COVID-19 severity/mortality and supports antioxidant/immune defenses; iodine (with LPO) shows broad antiviral support and immunomodulatory effects; copper has antiviral and immunoregulatory roles. - Overall, multiple milk components could act additively/synergistically as prophylactic or adjunctive therapies to mitigate viral entry, replication, hyperinflammation (cytokine storm), oxidative stress, and coagulopathy in COVID-19.

The compiled evidence suggests animal milk components target several key steps of SARS-CoV-2 pathogenesis: receptor binding and entry (via HSPG, ACE2, DPP-4 interference), proteolytic activation (furin, cathepsin L), protease function (3CLpro/Mpro inhibition), and downstream inflammatory and thrombotic cascades. This multi-target profile may afford activity across variants and complement existing antivirals. Immunomodulatory proteins (LF, WPs, caseins), enzymatic systems (LPO), glycans (MOs, GAGs), lipids (GML, EPA/DHA), and micronutrients collectively support innate and adaptive immunity, reduce oxidative stress and cytokine dysregulation, and may ameliorate ARDS and coagulopathy. While promising mechanisms and preclinical data exist, translation to clinical benefit in COVID-19 requires controlled trials to define effective formulations, doses, timing, and safety in diverse populations.

Animal milk harbors multiple bioactive constituents with antiviral, immunomodulatory, anti-inflammatory, antioxidant, and antithrombotic activities relevant to COVID-19. Lactoferrin may directly impede SARS-CoV-2 attachment/entry and augment antivirals; whey/casein peptides, mucins, LPO, and oligosaccharides can block entry or replication; GML and omega-3 PUFAs support antiviral defenses and resolution of lung inflammation; vitamins and minerals modulate immune and coagulation pathways. These components, individually or combined, could serve as inexpensive, widely available adjuncts to standard COVID-19 management to enhance recovery and resilience. Future work should prioritize rigorous in vitro/in vivo validation, pharmacokinetics, standardized preparations (species/source, processing), and well-designed clinical trials to establish efficacy, safety, and guidance for use.

Most evidence is preclinical (in vitro, in silico, animal models) with limited randomized clinical data directly in COVID-19. Composition of milk components varies by species, breed, diet, lactation stage, and processing, affecting bioactive content and bioavailability. Dosing, formulation, and delivery routes are not standardized. Certain constituents (e.g., iodine, Neu5Gc-containing glycans) may have context-dependent effects or safety considerations in specific populations. The narrative review design precludes quantitative synthesis and may be subject to selection bias; no new data were generated.